The Journal of clinical endocrinology and metabolism · 2026
Dysregulation of glycogen metabolism in cardiomyopathy caused by glycogenin-1 (GYG1) missense variants.
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Visuttijai Kittichate, Hedberg-Oldfors Carola, Braun Oscar, Englund Elisabet, Glamuzina Emma, Turner Clinton, Vukusic Kristina, Sandstedt Joakim, Dellgren Göran, Karason Kristjan, Oldfors Anders
Аннотация
CONTEXT: Glycogen storage diseases are inherited disorders of glycogen metabolism and are commonly associated with hypoglycaemia, hepatic dysfunction, or skeletal and cardiac myopathy, depending on the affected enzyme. Glycogen storage disease type 15 (GSD15) is caused by pathogenic variants in GYG1, which encodes glycogenin-1, the auto-glucosylating primer required for glycogen synthesis. GSD15 is characterized by cardiomyopathy and storage of abnormal glycogen and polyglucosan in cardiomyocytes.
OBJECTIVE: To understand the pathobiology of GSD15, we investigated the storage material in heart explants from two previously reported patients and describe a new case of GSD15.
METHODS: The characteristic storage material was investigated using laser capture microdissection followed by quantitative mass spectrometry (MS) and immunohistochemistry comparing differentially abundant proteins in the storage material with normal-appearing cytoplasmic regions from the same patient. Global protein dysregulation in GSD15 was assessed by quantitative MS of whole-myocardial tissue samples from patients and normal controls.
RESULTS: The storage material was enriched in proteins involved in glycogen metabolism, including glycogen synthase, UDP-glucose pyrophosphorylase 2, glycogenin-1, glycogen phosphorylase, and glycogen debranching enzyme. Sequestosome 1 (p62) and desmin were also enriched, without evidence of increased autophagocytosis. Whole-tissue analyses revealed upregulation of cardiomyopathy-associated biomarkers and downregulation of mitochondrial proteins, suggesting impaired energy metabolism contributing. to congestive heart failure.
CONCLUSIONS: In GSD15, storage of abnormal glycogen in cardiomyocytes is associated with enrichment of specific proteins involved in glycogen metabolism, contributing to dysregulation of glycogen turnover. This dysregulation results in polyglucosan accumulation, disruption of sarcomeric and mitochondrial architecture, and progressive fibrosis. No disease-modifying therapy currently exists for GSD15; future strategies based on substrate reduction, enhancement of autophagy, or gene therapy require further investigation.
OBJECTIVE: To understand the pathobiology of GSD15, we investigated the storage material in heart explants from two previously reported patients and describe a new case of GSD15.
METHODS: The characteristic storage material was investigated using laser capture microdissection followed by quantitative mass spectrometry (MS) and immunohistochemistry comparing differentially abundant proteins in the storage material with normal-appearing cytoplasmic regions from the same patient. Global protein dysregulation in GSD15 was assessed by quantitative MS of whole-myocardial tissue samples from patients and normal controls.
RESULTS: The storage material was enriched in proteins involved in glycogen metabolism, including glycogen synthase, UDP-glucose pyrophosphorylase 2, glycogenin-1, glycogen phosphorylase, and glycogen debranching enzyme. Sequestosome 1 (p62) and desmin were also enriched, without evidence of increased autophagocytosis. Whole-tissue analyses revealed upregulation of cardiomyopathy-associated biomarkers and downregulation of mitochondrial proteins, suggesting impaired energy metabolism contributing. to congestive heart failure.
CONCLUSIONS: In GSD15, storage of abnormal glycogen in cardiomyocytes is associated with enrichment of specific proteins involved in glycogen metabolism, contributing to dysregulation of glycogen turnover. This dysregulation results in polyglucosan accumulation, disruption of sarcomeric and mitochondrial architecture, and progressive fibrosis. No disease-modifying therapy currently exists for GSD15; future strategies based on substrate reduction, enhancement of autophagy, or gene therapy require further investigation.